It is well known that various kinds of proteases exist in living bodies. For example, the existence of a class of serine proteases such as thrombin, factor Xa, factor IXa, factor VIIa, trypsin, plasmin, tissue plasminogen activator, kallikrein, C1 enzyme in complement, C3/C5 convertase, and tryptase are known. It is also known that various kinds of diseases are caused when these proteases are abnormally activated by. Accordingly, substances having inhibitory activity against these proteases are expected to be useful as medicaments.
For example, it is known that antithrombotic agents are effective as therapeutic medicaments for thrombosis, and for this reason, developments of protease inhibitors having antithrombotic activity have been progressing. However, these inhibitors have several problems of, for example, insufficient stability in vivo or non-selectivity to serine proteases other than thrombin, or decrease of antithrombotic activity when administered orally. Therefore, the inhibitors are not satisfactory for practical applications.
Some tripeptide derivatives containing a moiety of arginine derivative are also known as protease inhibitors. For example, D-phenylalanyl-L-prolyl-L-arginal is known as a thrombin inhibitor (for example, Folia Haematol. 109, 22 (1982)). However, this compound is relatively unstable in a living body (J. Med. Chem., 33, 1729 (1990)). There are also several reports about arginal derivatives (Japanese Patent Unexamined Publication No. (Hei)4-89498/1992; and WO 9315756), amidinophenyl-alanine derivatives (Thromb. Res., 17, 425 (1980)), arginine ketoamide derivatives (WO 9408941), boron compound derivatives (For example, J. Biol. Chem., 265, 18289 (1990), Japanese Patent Unexamined Publication Nos. Hei 4-330094/1992 and (Hei)6-298795/1994, and WO 9425049). However, the derivatives have a problem in that they have low enzymatic selectivity among serine proteases belonging to thrombin homologue, in particular, trypsin. Guanidine derivatives (Japanese Patent Unexamined Publication No. (Hei)6-25195/1994) and tetrasubstituted cyclohexylamine derivatives (WO 9425051) were reported as thrombin-specific inhibitors, however, their efficacy cannot be expected by oral administration.
Under the above-described circumstances, the inventor of the present invention conducted various research to find substances which have practically satisfactory enzyme selectivity, oral availability, and stability in vivo, and are structurally novel. As a result, they found that the penicillaminamide derivatives set forth below have desired properties, and thus achieved the present invention.
The present invention provides penicillaminamide derivatives represented by the following general formula (I) and salts thereof, and hydrates thereof and solvates thereof: ##STR2##
wherein:
n represents 1 or 2; PA1 R.sup.1 represents a C.sub.1 -C.sub.10 alkyl group which may be substituted with a C.sub.3 -C.sub.10 cycloalkyl group or carboxyl group, a C.sub.6 -C.sub.10 aryl group which may be substituted, a C.sub.3 -C.sub.10 cycloalkyl group which may be substituted, or a C.sub.7 -C.sub.12 aralkyl group which may be substituted; PA1 R.sup.2 represents hydrogen atom, a C.sub.1 C.sub.10 alkyl group, a C.sub.7 -C.sub.12 aralkyl group which may be substituted, --COR.sup.4 (wherein R.sup.4 represents hydrogen atom, a C.sub.1 -C.sub.10 alkyl group, a C.sub.1 -C.sub.10 alkoxy group, a C.sub.6 -C.sub.10 aryl group which may be substituted, a C.sub.6 -C.sub.10 aryloxy group which may be substituted, a C.sub.3 -C.sub.10 cycloalkyl group which may be substituted, a C.sub.3 -C.sub.10 cycloalkyloxy group which may be substituted, a C.sub.7 -C.sub.12 aralkyl group which may be substituted, or a C.sub.7 -C.sub.12 aralkyloxy group), or --SO.sub.2 R.sup.5 (wherein R.sup.5 represents a C.sub.1 -C.sub.1 alkyl group, a C.sub.6 -C.sub.10 aryl group which may be substituted, a C.sub.3 -C.sub.10 cycloalkyl group which may be substituted, or a C.sub.7 -C.sub.12 aralkyl group which may be substituted), and PA1 R.sup.3 represents amino group or amidino group, provided that the compounds wherein:
R.sup.1 represents methyl group, R.sup.2 represents ethoxycarbonyl group, R.sup.3 represents amino group, and n represents 1; PA2 R.sup.1 represents methyl group, R.sup.2 represents methylsulfonyl group, R.sup.3 represents amino group, and n represents 1; PA2 R.sup.1 represents ethyl group, R.sup.2 represents methylsulfonyl group, R.sup.3 represents amino group, and n represents 1; and PA2 R.sup.1 represents isopropyl group, R.sup.2 represents ethoxycarbonyl group, R.sup.3 represents amidino group, and n represents 1 are excluded.
According to other aspects of the present invention, there are provided medicament comprising a substance selected from the group consisting of the aforementioned penicillaminamide derivatives and salts thereof, and hydrates thereof and solvates thereof; and pharmaceutical compositions comprising a substance selected from the group consisting of the aforementioned penicillaminamide derivatives and salts thereof, and hydrates thereof and solvates thereof as an active ingredient, together with a pharmaceutically acceptable carrier. The aforementioned medicaments and pharmaceutical compositions are useful for preventive and/or therapeutic treatment of diseases caused by hyperfunction of protease activity, for example, they are useful as antithrombotic agents, i.e., orally available anticoagulant agents. Protease inhibitors comprising a substance selected from the group consisting of the aforementioned penicillaminamide derivatives and salts thereof, and hydrates thereof and solvates thereof are also provided according to further aspect of the present invention.
According to still further aspects of the present invention, there are provided a use of a substance selected from the group consisting of the aforementioned penicillaminamide derivatives and salts thereof, and hydrates thereof and solvates thereof for the manufacture of the above-described pharmaceutical compositions; and a method for therapeutic treatment of a disease caused by hyperfunction of protease activity, which comprises administering to a patient a therapeutically and/or preventively effective amount of a substance selected from the group consisting of the aforementioned penicillaminamide derivatives and salts thereof, and hydrates thereof and solvates thereof.